Synthesis of Novel Pentacyclic Triterpenoid Derivatives that Induce Apoptosis in Cancer Cells through a ROS-dependent, Mitochondrial-Mediated Pathway

Betulinic acid (BA) and oleanolic acid (OA) are plant-derived conjugates found in various medicinal plants that have emerged as potential antitumor agents. Herein, a series of novel BA and OA derivatives were synthesized by conjugation with per-O- methylated-beta-cyclodextrin (PM-beta-CD), and their anticancer properties against a panel of three human cancer cell lines were evaluated. Two OA-PM-beta-CD conjugates (48 and 50) were observed to be the most potent conjugates against the three cell lines (MCF-7, BGC-823, and HL-60), with a 15-to 20-fold decrease in the IC50 values (IC50: 6.06-8.47 mu M) compared with their parental conjugate (OA). Annexin V-FITC/propidium iodide staining and Western blot analysis revealed that both conjugates induced apoptosis in HL-60 cells. Additionally, in the representative conjugate 48-treated HL-60 cells, a decrease in mitochondrial membrane potential and subsequent release of cytochrome c into the cytosol were observed, indicating the activation of the intrinsic apoptosis pathway. Furthermore, 48 dramatically induced the generation of reactive oxygen species (ROS) in HL-60 cells, and the corresponding effect could be reversed using the ROS scavenger N-acetylcysteine. Collectively, these results suggest that the novel pentacyclic triterpenoid derivatives trigger the intrinsic apoptotic pathways via the ROS-mediated activation of caspase-3 signaling, inducing cell death in human cancer cells.

Automated summary

In this study, a series of novel derivatives of betulinic acid (BA) and oleanolic acid (OA) were synthesized and evaluated for their anticancer properties. The results showed that two derivatives of OA exhibited the strongest antitumor activity against three human cancer cell lines. Further experiments revealed that these derivatives induced apoptosis in the cells through activation of the intrinsic apoptotic pathways mediated by reactive oxygen species (ROS) and caspase-3 signaling.